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Analysis of genetic susceptibility to cervical cancer using candidate gene and GWAS approaches
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Ulf Gyllensten)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cervical cancer is the forth most commonly diagnosed cancer among women worldwide. It is caused by persistent infection with an oncogenic type of Human Papillomavirus (HPV). The HPV is a necessary but not sufficient cause of cervical cancer. Environmental factors such as smoking, high parity and long-term use of oral contraceptives increases the risk of cervical cancer. Genetic factors also affect the risk of developing the disease. The aim of this thesis is to search for and evaluate genetic risk factors for cervical cancer using both a candidate gene approach and a genome-wide association study (GWAS).

Paper I examined the association of genetic variation in three Fanconi Anemia (FA) genes (FANCA, FANCC and FANCL), involved in DNA repair, with cervical cancer susceptibility in the Swedish population. No association was observed. Paper II evaluated the association of genetic variation in the TMC6 and TMC8 genes with susceptibility to cervical cancer in the Swedish population and an association of two SNPs (rs2290907 and rs16970849) with cervical cancer was observed.  In paper III the first GWAS performed in cervical cancer was reported. Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were found to affect the susceptibility to cervical cancer. Paper IV examined the sequence variation in the TMC6 and TMC8 region and its association with cervical cancer. A highly polymorphic 21 bp sequence was identified and found to be repeated 5 to 42 times in both cases and controls. Lack of this repeat was associated with increased risk of cervical cancer. An intronic SNP (rs2926778) located in between the TNRC6C and TMC6 genes was also found to be associated with cervical cancer.

The thesis provides evidence for the importance of genes in the immune system for cervical cancer susceptibility. The genetic risk factors identified explain only a part of the genetic susceptibility, implying that other risk factors remains to be identified

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1100
Keyword [en]
cervical cancer, association study, human papillomavirus, genetics, complex disease, TMC6, TMC8, MHC region
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-248484ISBN: 978-91-554-9234-2 (print)OAI: oai:DiVA.org:uu-248484DiVA: diva2:800835
Public defence
2015-05-28, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-05-06 Created: 2015-03-30 Last updated: 2015-07-07
List of papers
1. Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility
Open this publication in new window or tab >>Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility
2011 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 122, no 2, 377-381 p.Article in journal (Refereed) Published
Abstract [en]

Objective. Disrupting the function of any of the 13 Fanconi anaemia (FA) genes causes a DNA repair deficiency disorder, with patients being susceptible to a number of cancer types. Variation in the family of FA genes has been suggested to affect risk of cervical cancer. The current study evaluates the influence of three genes in the FA pathway on cervical cancer risk in Swedish women. Methods. TagSNPs in FANCA, FANCC and FANCL were selected using the Tagger algorithm in Haploview. A total of 81 tagSNPs were genotyped in 782 cases (CIN3 or ICC) and 775 controls using the Illumina GoldenGate Assay and statistically analyzed for association with cervical cancer. Results. 72 SNPs were successfully genotyped in >98% of the samples. Nominal associations were detected for FANCA rs11649196 (p = 0.05) and rs4128763 in FANCC (p = 0.02). The associations did not withstand correction for multiple testing. Conclusions. The current study does not support that genetic variation in FANCA, FANCC or FANCL genes affects susceptibility to cervical cancer in the Swedish population.

Keyword
Cervical cancer, FANCA, FANCC, FANCL, Fanconi anaemia, Genetic variants
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-158608 (URN)10.1016/j.ygyno.2011.04.014 (DOI)000293681800034 ()
Available from: 2011-09-12 Created: 2011-09-12 Last updated: 2017-12-08Bibliographically approved
2. Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility
Open this publication in new window or tab >>Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility
Show others...
2012 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 2, 349-355 p.Article in journal (Refereed) Published
Abstract [en]

Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)(GGvsAA) = 0.6, 95% confidence interval (95% CI): 0.3-0.9, p = 0.02)] and rs16970849 (OR(AGvsGG) = 0.8, 95% CI: 0.66-0.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

Keyword
cervical cancer, EVER1, EVER2, polymorphism, TMC6, TMC8
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-153612 (URN)10.1002/ijc.26016 (DOI)000298254400012 ()21387292 (PubMedID)
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2015-07-07Bibliographically approved
3. Genome-wide Association Study of Susceptibility Loci for Cervical Cancer
Open this publication in new window or tab >>Genome-wide Association Study of Susceptibility Loci for Cervical Cancer
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2013 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 105, no 9, 624-633 p.Article in journal (Refereed) Published
Abstract [en]

Background Cervical carcinoma has a heritable genetic component, but the genetic basis of cervical cancer is still not well understood. Methods We performed a genome-wide association study of 731 422 single nucleotide polymorphisms (SNPs) in 1075 cervical cancer case subjects and 4014 control subjects and replicated it in 1140 case subjects and 1058 control subjects. The association between top SNPs and cervical cancer was estimated by odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression. All statistical tests were two-sided. Results Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were associated with cervical cancer: the first is adjacent to the MHC class I polypeptide-related sequence A gene (MICA) (rs2516448; OR = 1.42, 95% CI = 1.31 to 1.54; P = 1.6 x 10(-18)); the second is between HLA-DRB1 and HLA-DQA1 (rs9272143; OR = 0.67, 95% CI = 0.62 to 0.72; P = 9.3 x 10(-24)); and the third is at HLA-DPB2 (rs3117027; OR=1.25, 95% CI = 1.15 to 1.35; P = 4.9 x 10(-8)). We also confirmed previously reported associations of B*0702 and DRB1*1501-DQB1*0602 with susceptibility to and DRB1*1301-DQA1*0103-DQB1*0603 with protection against cervical cancer. The three new loci are statistically independent of these specific human leukocyte antigen alleles/haplotypes. MICA encodes a membrane-bound protein that acts as a ligand for NKG2D to activate antitumor effects. The risk allele of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) of MICA, which results in a truncated protein. Functional analysis shows that women carrying this mutation have lower levels of membrane-bound MICA. Conclusions Three novel loci in the MHC may affect susceptibility to cervical cancer in situ, including the MICA-A5.1 allele that may cause impaired immune activation and increased risk of tumor development.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-202385 (URN)10.1093/jnci/djt051 (DOI)000318681200009 ()
Available from: 2013-06-24 Created: 2013-06-24 Last updated: 2017-12-06Bibliographically approved
4. Characterization of the TMC6 and TMC8 (EVER1 and EVER2) genes associated with cervical cancer
Open this publication in new window or tab >>Characterization of the TMC6 and TMC8 (EVER1 and EVER2) genes associated with cervical cancer
(English)Manuscript (preprint) (Other academic)
Keyword
Cervical cancer, CNV, TMC6, TMC 8, HPV
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-248481 (URN)
Available from: 2015-03-30 Created: 2015-03-30 Last updated: 2015-07-07

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